MIT scientists have made a significant advancement in improving the efficacy of chimeric antigen receptor (CAR) T cell therapy for treating solid tumors. By utilizing a vaccine to amplify the response of engineered T cells and stimulate the immune system to target different tumor antigens, they have successfully tackled the challenge of antigen variation, a major hurdle in solid tumor treatment.
CAR T cell therapy, which involves modifying T cells to eliminate cancer cells, has demonstrated success in certain cancers like leukemia and lymphoma but has proven less effective against solid tumors.
The limited success in treating solid tumors is partly attributed to the fact that T cells only target a single antigen, a specific protein found on tumor cells. If some tumor cells do not express that particular antigen, they can evade the T cell attack.
The MIT researchers have now devised a method to overcome this obstacle by employing a vaccine that enhances the response of CAR T cells and facilitates the generation of new T cells by the immune system, which can target additional tumor antigens. In mouse studies, this approach significantly increased the likelihood of tumor eradication.
“This vaccine boosting appears to trigger antigen spreading, where the immune system collaborates with engineered CAR T cells to reject tumors in which not all cells express the antigen targeted by the CAR T cells,” explains Darrell Irvine, the Underwood-Prescott Professor at MIT’s departments of Biological Engineering and Materials Science and Engineering, and a member of MIT’s Koch Institute for Integrative Cancer Research and the Ragon Institute of MGH, MIT, and Harvard.
The study, led by Leyuan Ma, a former postdoc at the Koch Institute and currently an assistant professor at the University of Pennsylvania School of Medicine, and senior author Darrell Irvine, was published in the journal Cell on July 5, 2023.
CAR T Cells:
Various types of T cell therapies based on CAR T cells have received approval from the U.S. Food and Drug Administration for treating blood cancers. These therapies involve engineering T cells to express receptors that can identify specific antigens on cancer cells.
To adapt this treatment approach to glioblastoma, a type of brain cancer, researchers have designed CAR T cells that target a mutated version of the EGFR receptor. However, not all glioblastoma cells express this antigen, and some cells halt production of the targeted antigen when attacked by CAR T cells.
In a previous study conducted in 2019, Irvine and his team enhanced the effectiveness of CAR T cells against glioblastoma by administering a vaccine to mice shortly after introducing the engineered T cells. This vaccine carries the same antigen targeted by CAR T cells and is taken up by immune cells in the lymph nodes, where the CAR T cells are exposed to it.
The researchers discovered that the vaccine boost not only helped the engineered CAR T cells attack tumors but also stimulated the generation of host T cells that target other tumor antigens.
This phenomenon, referred to as “antigen spreading,” is desirable as it creates populations of T cells that can collaboratively eliminate tumors and prevent tumor regrowth.
“This could be a solution for addressing the antigen diversity of solid tumors since priming host T cells to attack other antigens may enable them to kill the tumor cells that CAR T cells cannot,” says Irvine.
Immune Enhancement:
In their latest study, the researchers investigated how this additional T cell response is activated. They employed the same CAR T cells used in their 2019 study, which target mutant EGFR, and administered the same vaccine to mice. The mice received two doses of the vaccine, one week apart.
The researchers observed metabolic changes in the CAR T cells of the boosted mice, leading to increased production of interferon gamma, a cytokine that stimulates a robust immune response. This helps the T cells overcome the immunosuppressive environment within the tumor, which typically inhibits nearby T cells.
As the CAR T cells killed tumor cells expressing the target antigen, host T cells (non-engineered CAR T cells) encountered other antigens from the tumor cells, prompting these host T cells to target those antigens and aid in the destruction of tumor cells.
The researchers discovered that without the response from host T cells, tumors would regrow even if the CAR T cells destroyed the majority of the original tumor cells. This occurs because tumor cells treated with CAR T cells often cease production of the antigen targeted by the engineered cells, allowing them to evade detection.
Tumor Eradication:
Next, the researchers tested their approach on mice with tumors expressing different levels of the target antigen. They found that even in tumors where only 50 percent of the cells expressed the target antigen, approximately 25 percent of the tumors could still be eradicated through a combination of CAR T cells and host T cells.
The success rate was higher for tumors with higher levels of the target antigen. When 80 percent of the tumor cells expressed the CAR T cell-targeted antigen, approximately 80 percent of the mice exhibited complete tumor elimination.
The technology employed in this study has been licensed to Elicio Therapeutics, a company focused on its development for potential testing in patients. While the researchers primarily focused on glioblastoma and melanoma, they believe the approach could be applicable to other cancer types as well.
“In theory, this approach could be applied to any solid tumor that can be targeted by CAR T cells,” Irvine concludes.
The study received funding from the National Institutes of Health, the Marble Center for Cancer Nanomedicine at the Koch Institute, The Mark Foundation for Cancer Research (ASPIRE Award), the American Cancer Society (postdoctoral fellowship), the Cell and Gene Therapy Collaborative at the Children’s Hospital of Philadelphia, the W.W. Smith Charitable Trust, and a Koch Institute Support Grant from the National Cancer Institute.
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Frequently Asked Questions (FAQs) about CAR T cell therapy
What is CAR T cell therapy?
CAR T cell therapy is a type of immunotherapy where T cells are engineered to express receptors called chimeric antigen receptors (CARs) that can recognize specific antigens on cancer cells. These modified T cells are then infused back into the patient’s body to target and destroy cancer cells.
What are the challenges of CAR T cell therapy in treating solid tumors?
One major challenge is antigen variation. Solid tumors can have heterogeneity in antigen expression, meaning not all tumor cells express the target antigen. This can lead to tumor cells evading the attack of CAR T cells, reducing the effectiveness of the therapy.
How have MIT researchers addressed the issue of antigen variation in CAR T cell therapy?
MIT researchers have developed a strategy using a vaccine to enhance the response of CAR T cells and stimulate the immune system to target various tumor antigens. This approach helps overcome antigen variation by generating host T cells that can target other tumor antigens, increasing the likelihood of tumor eradication.
What is antigen spreading?
Antigen spreading refers to a phenomenon where the immune system, in collaboration with engineered CAR T cells, generates T cells that target additional tumor antigens beyond the original CAR T cell target. This is desirable as it creates a broader immune response against the tumor, improving the chances of complete tumor eradication.
Can this approach be applied to other types of cancer?
Yes, the researchers believe that this approach can be applied to other solid tumors as well. In principle, as long as a CAR T cell can be generated to target a specific tumor, the vaccine-boosting strategy can be used to enhance the immune response and improve treatment outcomes.
Is there potential for clinical application?
Yes, the technology used in this research has been licensed to a company called Elicio Therapeutics, which is working on developing it for potential testing in patients. While the focus has been on glioblastoma and melanoma, the approach holds promise for other types of cancer as well.
More about CAR T cell therapy
- MIT News: Solid Tumor Eradication: MIT’s Vaccine Delivers a Boost to T Cell Cancer Treatment
- Study Publication in Cell: Vaccine-boosted CAR T crosstalk with host immunity to reject tumors with antigen heterogeneity
- MIT Koch Institute for Integrative Cancer Research: Research Highlights
- University of Pennsylvania School of Medicine: Leyuan Ma’s Research Profile
- Elicio Therapeutics: Company Website
5 comments
antigen spreading sounds so promising. the immune system teaming up with CAR T cells to fight tumors is incredible. kudos to the scientists for their hard work and innovation!
omg this is amazing! mit researches found a way 2 boost car t cells with a vaccine? that’s so cool! i hope they can use it 2 treat other cancers 2!
CAR T cell therapy is so fascinating! MIT researchers rly know their stuff. antigen variation is a big problem, so it’s great they found a way around it. hoping this brings new hope to cancer patients!
wow MIT is always on the cutting edge! this research could be a game-changer for solid tumor treatment. can’t wait to see how it progresses in clinical trials!
as someone battling cancer, this gives me hope. knowing that researchers are working on improving treatment options like CAR T cell therapy is inspiring. keep pushing the boundaries of science!